Modern stereological techniques have been used to show that the total length of the cholinergic fibers in the cerebral cortex of the APPswe/PS1deltaE9 mouse is reduced by almost 300 meters at 18 months of age and has a nonlinear relationship to the amount of transgenetically-induced amyloidosis. These data provide rigorous quantitative morphological evidence that Alzheimer's-like amyloidosis affects the axons of the cholinergic enervation of the cerebral cortex.
Disturbances in the cholinergic enervation of the brain are consistent features of Alzheimer's disease (AD). These include the loss of cholinergic neurons in the basal forebrain and reductions in the cholinergic markers in the cerebral cortex and hippocampal region (Davies and Maloney, 1976, Mufson et al., 1987 and Whitehouse et al., 1981). Cholinergic axons from basal forebrain neurons (Mesulam et al., 1983) synapse directly on principal and interneurons in cortex (Freund and Buzsáki, 1996) and presynaptically regulate a number of transmitter systems (Vizi and Kiss, 1998). These disturbances can be expected to contribute to the cognitive decline that accompanies AD. Although there is accumulating evidence that disturbances in axonal transport-related AD amyloidosis, are involved (Salehi et al., 2007), the quantitative relationship between the amyloidosis associated with AD and disturbances in the cholinergic system is not clear.
Transgenic mouse models of AD-like amyloidosis that harbor genes related to mutations found in familial forms of AD, similarly show evidence of disturbances found in the cholinergic systems. These include reductions in acetylcholine (ACh) markers (Savonenko et al., 2005), including choline acetly-transferase (ChAT) (Perez et al., 2007) and vesicular acetylcholine transporter (VAChT)-positive boutons (Wong et al., 1999); aberrant cholinergic fibers in the vicinity of amyloid plaques (Boncristiano et al., 2002 and Perez et al., 2007); decreases in the density of ACh fibers (Perez et al., 2007) and synaptic vericosities (Boncristiano et al., 2002 and Bronfman et al., 2000); and increases in the size of cell bodies (Boncristiano et al., 2002, Perez et al., 2007 and Salehi et al., 2007). In many of these models, including the APP/PS1deltaE9 mouse model studied here, these disturbances occur in the absence of neuron and synapse loss in glutamatergic systems (Volianskis et al., 2010 and West et al., 2009). The relative specificity of these alterations in the APP/PS1deltaE9 mouse provide an opportunity to study the cellular mechanisms by which aberrant amyloid metabolism results in neurodegenerative changes in the cholinergic system, to dissect their inductive and responsive roles in the pathogenesis of AD, and to better understand the basis of the selective vulnerability of the cholinergic fibers.
To provide a more rigorous structural framework in which to study the effect of AD like amyloidosis on the cholinergic enervation of the forebrain, we have estimated the total length of the cholinergic fibers in the cerebral cortex of a transgenic mouse model of AD like amyloidosis at 3 different ages.
